Inflammation is the final common pathway of various insults, such as infection, trauma, and allergies to the human body. It is characterized by activation of the immune system with recruitment and activation of inflammatory cells and production of pro-inflammatory mediators.
Most inflammatory diseases are characterized by enhanced accumulation of differing proportions of inflammatory cells, including monocytes/macrophages, granulocytes, plasma cells, lymphocytes and platelets. Along with tissue endothelial cells and fibroblasts, these inflammatory cells release a complex array of lipids, growth factors, cytokines and destructive enzymes that cause local tissue damage.
One form of inflammatory response is neutrophilic inflammation which is characterized by infiltration of the inflamed tissue by neutrophilic polymorphonuclear leukocytes (PMN, i.e. neutrophils), which are a major component of host defence. Neutrophils are activated by a great variety of stimuli and are involved in a number of clinical conditions and diseases where they play a pivotal role. Such diseases may be classified according to the major neutrophil-activating event (Table 3, page 638 of V. Witko-Sarsat et al., Laboratory Investigation (2000) 80(5), 617-653). Tissue infection by extracellular bacteria represents the prototype of this inflammatory response. On the other hand, various non-infectious diseases are characterized by extravascular recruitment of neutrophils. These non-infectious inflammatory diseases may be the result of an intermittent resurgence (e.g. flare in autoimmune diseases such as rheumatoid arthritis), or continuous generation (e.g. chronic obstructive pulmonary disease (COPD)) of inflammatory signals arising from underlying immune dysfunction. Non-infectious inflammatory disease include COPD, cystic fibrosis (CF), diffuse panbronchiolitis (DPB), bronchiolitis obliterans (BOS), bronchitis, bronchiectasis, emphysema, acute respiratory distress syndrome (ARDS, known also as adult respiratory distress syndrome or respiratory distress syndrome, RDS), as well as glomerulonephritis, rheumatoid arthritis, gouty arthritis, ulcerative colitis, certain dermatoses such as psoriasis and vasculitis. In these conditions neutrophils are thought to play a crucial role in the development of tissue injury which, when persistent, can lead to the irreversible destruction of the normal tissue architecture with consequent organ dysfunction. Consequently, correlation between neutrophil number in sputum or bronchoalveolar lavage fluid and disease severity and decline in lung function is demonstrated in patients with chronic obstructive pulmonary disease (Di Stefano et al., Am J Respir Crit. Care Med. (1998), 158(4): 1277-1285), cystic fibrosis (Sage) SD et al., J Pediatr. (2002), 141(6): 811-817), diffuse panbronchiolitis (Yanagihara K et al., Int J Antimicrob Agents. (2001), 18 Suppl 1: S83-87), bronchiolitis obliterans (Devouassoux G et al., Transpl Immunol. (2002), 10(4): 303-310), bronchitis (Thompson A B et al., Am Rev Respir Dis. (1989), 140(6): 1527-1537), bronchiectasis (Sepper R et al., Chest (1995), 107(6): 1641-1647), acute respiratory distress syndrome (Weiland J E et al., Am Rev Respir Dis. (1986), 133(2): 218-225), to name a few. In addition, there is increasing evidence of neutrophil inflammation in asthmatics, particularly in patients with severe disease and patients who smoke (Jatakanon A et al., Am J Respir Crit. Care Med. (1999), 160: 1532-1539; Chalmers G W et al., Chest (2001), 120: 1917-1922). Evidence of the importance of neutrophils in several lung diseases has prompted a search for drugs that inhibit neutrophilic infiltration into lungs and consequent inflammation (reviewed in Barnes P J, J Allergy Clin Immunol. (2007), 119(5): 1055-1062).
It is known that many antibiotics, in particular the class of erythromycin-based macrolides, have anti-inflammatory properties in addition to their antibacterial activity (Clin. Immunother. (1996) 6, 454-464), J. Antimicrob. Chemother. (1998) 41, Suppl. B 37-46). In the international patent application publication WO02/087596 (Pliva) the anti-inflammatory activity of azithromycin, a 15-membered azalide antibacterial agent, has been described. Thus, the interest of the scientific community has turned towards the anti-inflammatory and immunomodulatory properties of erythromycin and derivatives thereof (J. Antimicrob. Chemother. (1998), 41, Suppl. B, 37-46). This activity is well documented both in clinical studies and in in vivo and in vitro experiments. For example, macrolides have been found to be effective in the treatment of inflammatory diseases such as panbronchiolitis (Thorax (1997), 52, 915-918), bronchial asthma (Chest, (1991), 99, 670-673) and cystic fibrosis (The Lancet (1998) 351, 420), both in animal models of inflammation, for instance zymosan-induced peritonitis in mice (J. Antimicrob. Chemother. (1992) 30, 339-348) and endotoxin-induced accumulation of neutrophils in rat trachea (Antimicrobial Agents and Chemotherapy (1994) 38, 1641-1643], and in in vitro studies on immune system cells, such as neutrophils (J. Immunology (1997) 159, 3395-4005).
The particular therapeutic efficacy of macrolide compounds in diseases where conventional anti-inflammatory drugs, for instance corticosteroids, have been found to be ineffective (Thorax (1997) 52, 915-918, already cited) justifies the great interest in this new potential class of anti-inflammatories. However, the strong antibacterial activity that conventional macrolide compounds have does not allow their broader use in the chronic treatment of inflammatory processes not caused by pathogenic microorganisms, since this could give rise to the rapid development of resistant strains.
Based on the foregoing, there exists a significant need to identify compounds having a biological profile which demonstrates the ability to inhibit neutrophil dominated inflammation whilst not having anti-bacterial activity. Such compounds should also have a stability which renders them suitable for development as a therapeutic treatment.
WO06/87644 discloses macrolide compounds represented by Formula (I) below:
wherein    A is a bivalent radical selected from —C(O)—, —NHC(O)—, —C(O)NH—, —N(R7)CH2—, —CH2N(R7)—, —CH(OH)— and —C(═NOR7)—;    R1 is —OC(O)(CH2)nNR8R9, —O—(CH2)nNR8R9, —OC(O)N(R7)(CH2)nNR8R9,
—O(CH2)nCN, —OC(O)(CH2)nN(CH2)nNR8R9, or —OC(O)CH═CH2 with the proviso that if R1 is —OC(O)CH═CH2, R3 cannot be methyl;    R2 is hydrogen or a hydroxyl protecting group;    R3 is hydrogen, unsubstituted C1-4 alkyl or C1-4 alkyl substituted at terminal carbon atom with CN or NH2 group, or C1-5 alkanoyl;    R4 is hydrogen, C1-4 alkyl or C2-6 alkenyl or a hydroxyl protecting group 1;    R5 is hydroxy, methoxy group, —OC(O)(CH2)nNR8R9—O—(CH2)nNR8R9 or —O(CH2)nCN;    R6 is hydroxy; or    R5 and R6 taken together with the intervening atoms form a cyclic group having the following structure:
    wherein Y is a bivalent radical selected from —CH2—, —CH(CN)—, —O—, —N(R7)— and —CH(SR7)—;    R7 is hydrogen or C1-6alkyl;    R8 and R9 are each independently hydrogen, C3-7 cycloalkyl, C1-18 alkyl, wherein C1-18 alkyl is:    (i) uninterrupted or interrupted by 1-3 bivalent radical groups selected from —O—, —S— and —N(R7)—; and/or    (ii) unsubstituted or substituted by 1-3 groups selected from halogen, OH, NH2, N—(C1-C6)alkylamino (preferably N-methylamino or N-ethylamino), N,N-di(C1-C6-alkyl)amino (preferably dimethylamino, diethylamino or di-isopropylamino), CN, NO2, OCH3, a C3-8 membered non-aromatic ring which is saturated or unsaturated a non-aromatic heterocyclic ring containing 2-6 carbon atoms which is saturated or unsaturated containing from 1-2 heteroatoms selected from oxygen, sulphur and nitrogen, alkylcarbonylalkoxy and alkoxycarbonylamino; orR8 and R9 taken together with nitrogen to which they are attached form a non-aromatic heterocyclic ring containing 2-6 carbon atoms which is:            i) saturated or unsaturated containing from 0 or 1 additional heteroatoms selected from oxygen, sulphur and nitrogen; and/or        ii) unsubstituted or substituted by 1-2 groups selected from C1-3alkanoyl and C1-6alkyl, wherein C1-6alkyl is uninterrupted or is interrupted by 1-3 bivalent radical groups selected from —O—, —S— and —N(R7)—, and/or being unsubstituted or substituted by 1-2 groups selected from OH, NH2, a non-aromatic heterocyclic ring containing 2-6 carbon atoms which is unsubstituted or is substituted by group selected from C1-4 alkyl, halo, NH2, OH, SH, C1-6 alkoxy and C1-4 hydroxyalkyl, a C3-7 cycloalkyl which is unsubstituted or is substituted by group selected from C1-4 alkyl, halo, NH2, OH, SH, C1-6alkoxy and C1-4 hydroxyalkyl;            n is an integer from 1 to 8;and pharmaceutically acceptable derivatives thereof. It describes these compounds as having anti-inflammatory activity.